Identification of a Post-translational Modification With Ribitol-Phosphate and Its Defect in Muscular Dystrophy

Cell Rep. 2016 Mar 8;14(9):2209-2223. doi: 10.1016/j.celrep.2016.02.017. Epub 2016 Feb 25.

Abstract

Glycosylation is an essential post-translational modification that underlies many biological processes and diseases. α-dystroglycan (α-DG) is a receptor for matrix and synaptic proteins that causes muscular dystrophy and lissencephaly upon its abnormal glycosylation (α-dystroglycanopathies). Here we identify the glycan unit ribitol 5-phosphate (Rbo5P), a phosphoric ester of pentose alcohol, in α-DG. Rbo5P forms a tandem repeat and functions as a scaffold for the formation of the ligand-binding moiety. We show that enzyme activities of three major α-dystroglycanopathy-causing proteins are involved in the synthesis of tandem Rbo5P. Isoprenoid synthase domain-containing (ISPD) is cytidine diphosphate ribitol (CDP-Rbo) synthase. Fukutin and fukutin-related protein are sequentially acting Rbo5P transferases that use CDP-Rbo. Consequently, Rbo5P glycosylation is defective in α-dystroglycanopathy models. Supplementation of CDP-Rbo to ISPD-deficient cells restored α-DG glycosylation. These findings establish the molecular basis of mammalian Rbo5P glycosylation and provide insight into pathogenesis and therapeutic strategies in α-DG-associated diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Carbohydrate Conformation
  • Carbohydrate Sequence
  • Glycosylation
  • HEK293 Cells
  • Humans
  • Membrane Proteins / physiology*
  • Muscular Dystrophies / enzymology*
  • Muscular Dystrophies / genetics
  • Mutation
  • Nucleotidyltransferases / genetics
  • Pentosephosphates / metabolism*
  • Pentosyltransferases
  • Protein Processing, Post-Translational*
  • Proteins / physiology*

Substances

  • FKTN protein, human
  • Membrane Proteins
  • Pentosephosphates
  • Proteins
  • ribitol-5-phosphate
  • FKRP protein, human
  • Pentosyltransferases
  • Nucleotidyltransferases
  • CRPPA protein, human